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Understanding the role of the RNA helicase Upf1 in eukaryotic gene expression


   School of Biosciences

   Applications accepted all year round  Competition Funded PhD Project (Students Worldwide)

About the Project

UPF1 is a universally conserved RNA helicase in eukaryotes. We recently reported that UPF1 is a mobile protein in all cell compartments and that constantly shuttles between nucleus and cytoplasm, with its intracellular distribution reflecting that of the mRNA, which is characteristically more abundant in the cytoplasm than in the nucleus. Crucially, our observations show that UPF1 associates with nascent pre-mRNA transcripts and that it plays genome-wide roles in nuclear RNA-based processes – including Pol II pausing, mRNA export and most strikingly transcription site retention. These observations radically change our understanding of the roles of UPF1 protein in gene expression and convert UPF1 from a specialised mRNA decay factor to being a global player in mRNA based processes both in the nucleus and in the cytoplasm. The proposed research aims to unveil the specific molecular function(s) that UPF1 performs on ribonucleoprotein (RNP) complexes, and how might these function help to explain why mutations that affect its expression cause disease; and in particular, why even a modest over-expression of UPF1 can restore motoneurons functionality in a rat model of ALS, a deadly neurodegenerative disease for which there is no satisfactory treatment.

Techniques that will be undertaken during the project:

The project will involve advanced molecular biology, yeast (or Drosophila) molecular genetics and genomics techniques - including bioinformatics.

PI: Dr Saverio Brogna, University of Birmingham


Funding Notes

Funding notes:
Apply under the normal Bioscience PhD and put BBSRC Midlands Integrative Biosciences Training Partnership (MIBTP) DTP as their funding. Any applications with BBSRC funding will be picked up and the programme name can be changed at a later point. For more information, please visit out homepage: View Website

References

References:
1. Singh AK, Choudhury SR, De S, Zhang J, Kissane S, Dwivedi V, Ramanathan P, Petric M, Orsini L, Hebenstreit D, Brogna S. The RNA helicase UPF1 associates with mRNAs co-transcriptionally and is required for the release of mRNAs from gene loci. Elife. 2019 Mar 25;8. pii: e41444. doi: 10.7554/eLife.41444.

2. De S, Edwards DM, Dwivedi V, Wang J, Varsally W, Dixon HL, Singh AK, Owuamalam PO, Wright MT, Summers RP, Hossain MN, Price EM, Wojewodzic MW, Falciani F, Hodges NJ, Saponaro M, Tanaka K, Azzalin CM, Baumann P, Hebenstreit D, Brogna S. Genome-wide chromosomal association of Upf1 is linked to Pol II transcription in Schizosaccharomyces pombe. Nucleic Acids Res. 2022 Jan 11;50(1):350-367.

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